== What is Huntington’s disease? == Huntington’s disease is an inherited disease that causes the progressive dying off, or degeneration, of nerve cells in certain parts of the brain. American physician George Huntington wrote the first thorough description of Huntington’s disease (HD) in 1872, calling it “hereditary chorea” to underscore some of its key features. Chorea1 is derived from the Greek word for dance and describes the uncontrollable dance-like movements seen in people with HD. The hereditary nature of HD helps distinguish it from other types of chorea with infectious, metabolic, or hormonal causes. Understanding the hereditary nature of HD eventually enabled modern researchers to pinpoint the cause of the disease–a mutation or misspelling in a single gene.
More than 30,000 Americans have HD. Although the mutation is present from birth, symptoms of HD typically appear in middle age (adult HD), and in rare cases they appear in children (juvenile HD). The disease, which gets progressively worse, attacks motor control regions of the brain, as well as other areas. Chorea, abnormal body postures, and impaired coordination are among the most visible symptoms. But HD also causes changes in emotion and cognition (thinking) that can be devastating for people with the disorder and for their families.
Although there is no cure for HD, treatments are available to help manage its symptoms and other potential treatments are under investigation to slow or stop its course. And there are now genetic tests available for HD, which gives people at risk for the disease the option to plan for their health and the health of future generations.
How does HD affect the brain?
The most severe loss of nerve cells (also called neurons) occurs in deep brain structures called the basal ganglia, especially in a part of the basal ganglia called the striatum. The basal ganglia have a variety of functions, including helping to control voluntary (intentional) movement. Subsections of the basal ganglia, called the caudate nuclei and putamen, are most severely affected. Another strongly affected area is the brain’s outer surface, or cerebral cortex, which has important roles in movement, as well as thought, perception, memory, and emotion. As HD progresses over time, neuronal degeneration becomes more widespread throughout the brain. In addition to metabolic changes, there is degeneration in areas of the brain that control hormones.
How is HD inherited?
HD is passed from parent to child through a mutation in a gene. Genes contain the blueprint for who we are, from our outer appearance to the composition and workings of our internal organs, including the brain. The gene responsible for HD lies on chromosome 4.
When a parent has HD, each child has a 50 percent chance of inheriting the copy of chromosome 4 that carries the HD mutation. If a child does not inherit the HD mutation, he or she will not develop the disease and cannot pass it to subsequent generations. In some families, all the children may inherit the HD gene; in others, none do. Whether one child inherits the gene has no bearing on whether others will or will not share the same fate. A person who inherits the HD mutation and survives long enough will develop the disease.
To understand the HD gene mutation, it helps to know a little more about what genes are and what they do. Genes contain the instructions for making the approximately one million proteins that run everything in our bodies. The HD gene makes an essential protein called huntingtin, whose function is largely unknown but may be necessary for early nerve cell development. Huntingtin is most active in the brain. Genes are composed of deoxyribonucleic acid (DNA), a long chain-like molecule. The links in a DNA chain are called bases, or nucleotides, and there are four varieties—adenine, thymine, cytosine, and guanine—typically abbreviated as A, T, C, and G. Within each gene, a unique combination of these nucleotides serves as a code that determines the gene’s function; changes in the code—such as through a mutation—can change a gene’s function.
The disease-causing mutation inside the HD gene consists of a three-base sequence repeated many times. This type of mutation, called a triplet (or trinucleotide) repeat expansion, is responsible for dozens of other neurological diseases, but in each case the three-base sequence, or triplet, resides within a different gene. The triplet sequences also vary; in HD, the triplet consists of the bases C-A-G. Most people have fewer than 27 CAG repeats in the HD gene and are not at risk for the disease. Individuals with the disease may have 36 or more repeats. People who have repeats in the intermediate range (27-35) are unlikely to develop the disease, but they could pass it on to future generations.
|Number of CAG repeats||Outcome|
|< 26||Normal range; individual will not develop HD|
|27-35||Individual will not develop HD but the next generation is at risk|
|35-39||Some, but not all, individuals in this range will develop HD; next generation is also at risk|
|> 40||Individual will develop HD|
When HD occurs without a family history, it is called sporadic HD. These cases can occur when one parent has an intermediate range of CAG repeats, sometimes called a premutation. Prior to conception of a child, the number of repeats may expand into the disease-causing range. Most often, these expansions occur in the father’s sperm cells, rather than in the mother’s egg cells. Each time the father’s DNA is copied to make new sperm, there is a possibility for the number of CAG repeats to expand. This increase in disease severity from one generation to the next—with a younger onset and faster progression—is called anticipation.
What are the major effects of the disease?
Early signs of the disease vary greatly from person to person, but typically include cognitive or psychiatric symptoms, difficulties with movement, and behavioral changes. Symptoms of Huntington’s disease include:
- Behavioral changes. The individual experiences mood swings or becomes uncharacteristically irritable, apathetic, passive, depressed, or angry. These symptoms may lessen as the disease progresses or, in some individuals, may continue and include hostile outbursts, thoughts of suicide, deep bouts of depression, and, rarely, psychosis. Social withdrawal is common.
- Cognitive/judgment changes. HD may affect a person’s judgment, attention, and other cognitive functions. Early signs might include having trouble with driving, problem-solving or decision making, prioritizing tasks, and difficulty organizing, learning new things, remembering a fact, putting thoughts into words, or answering a question. Familiar tasks that were simple to complete when healthy now take longer or cannot be done at all. As the disease progresses, these cognitive problems worsen and affected individuals are no longer able to work, drive, or care for themselves. When the level of cognitive impairment is significant enough to impair daily functioning, it is described as dementia. Many people, however, remain aware of their environment and are able to express emotions. Some individuals cannot recognize other family members.
- Uncontrolled and difficult movement. Movement problems may begin with uncontrolled movement in the fingers, feet, face, or trunk. These movements, which are signs of chorea, often intensify when the person is anxious or distracted and become larger and more apparent over time. HD can also begin with mild clumsiness or problems with balance. Some people develop chorea-related movements. Chorea often creates serious problems with walking, increasing the likelihood of falls. Some individuals with HD do not develop chorea; instead, they may become rigid and move very little, or not at all, a condition called akinesia. Others may start out with chorea but become rigid as the disease progresses. In addition to chorea, some individuals have unusual fixed postures, called dystonia. The two movement disorders can blend or alternate. Other symptoms may include tremor (unintentional rhythmic muscle movement in a back-and-forth manner) and abnormal eye movements that often occur early.
- Physical changes. Speech becomes slurred and vital functions, such as swallowing, eating, speaking, and especially walking, continue to decline. Many people with HD lose weight as they encounter problems with feeding, swallowing, choking, and chest infections. Other symptoms may include insomnia, loss of energy, and fatigue. Some individuals with HD develop seizures. Eventually the person will be confined to a bed or wheelchair.
In general, the duration of the illness ranges from 10 to 30 years. The most common causes of death are infection (most often pneumonia) and injuries related to falls.
At what age does HD appear?
The rate of disease progression and the age at onset vary from person to person. As a general rule, having a higher number of CAG repeats is associated with an earlier onset and faster course of the disease. A common observation is that the earlier the symptoms appear, the faster the disease progresses.
Adult-onset HD most often begins between ages 30-50. A few individuals develop HD after age 55. Diagnosis in these people can be very difficult. The symptoms of HD may be masked by or confused with other health problems, or the person may not display the severity of symptoms seen in individuals with HD of earlier onset. These individuals may also show symptoms of depression rather than anger or irritability, or they may retain sharp control over their intellectual functions, such as memory, reasoning, and problem-solving.
There is also a related disorder called senile chorea. Some elderly individuals develop choreic movements, but do not become demented, have a normal HD gene, and lack a family history of the disorder. Some scientists believe that a different gene mutation may account for this small number of cases, but this has not been proven.
Some individuals develop symptoms of HD before age 20. This is called early-onset or juvenile HD. A common early sign of juvenile HD is a rapid decline in school performance. Movement problems soon become apparent, but they differ from the chorea typically seen in adult-onset HD. One common motor symptom in juvenile HD is myoclonus, which involves rapid involuntary muscle twitches or jerks. Other motor symptoms typical in juvenile HD include slowness, rigidity (in which the muscles remain constantly tense), and tremor. This constellation of symptoms can resemble Parkinson’s disease, and is sometimes called “akinetic-rigid” HD or the Westphal variant of HD. People with juvenile HD may also have seizures and mental disabilities. The earlier the onset, the faster the disease seems to progress. The disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years.
Individuals with juvenile HD usually inherit the disease from their fathers, who typically have a later onset form of HD themselves. To verify the link between the number of CAG repeats in the HD gene and the age at onset of symptoms, scientists studied a boy who developed HD symptoms at the age of two, one of the youngest and most severe cases ever recorded. They found that he had nearly 100 repeats. The boy’s case was central to the identification of the HD gene and at the same time helped confirm that juveniles with HD have the longest segments of CAG repeats. This correlation has been confirmed in other studies.
How is HD diagnosed?
A diagnosis of Huntington’s disease is generally based on findings from neurological, psychological, and genetic testing.
- Neurological tests. A neurologist will interview the individual intensively to obtain the medical history and rule out other conditions. Tests of neurological and physical functions may review reflexes, balance, movement, muscle tone, hearing, walking, and mental status. A number of laboratory tests may be ordered as well, and individuals with HD may be referred to other health care professionals such as psychiatrists, genetic counselors, clinical neuropsychologists, or speech pathologists for specialized management and/or diagnostic clarification. A tool used by physicians to diagnose HD is to take the family history, sometimes called a pedigree or genealogy. It is extremely important for family members to be candid and truthful with a professional who is taking a family history since another family member(s) may not have been accurately diagnosed with the disease but thought to have other issues.
- Genetic tests. The most effective and accurate method of testing for HD—called the direct genetic test—counts the number of CAG repeats in the HD gene, using DNA taken from a blood sample. The presence of 36 or more repeats supports a diagnosis of HD. A test result of 26 or fewer repeats rules out HD. A small percentage of individuals will have repeats in a borderline range. For such individuals, doctors may try to get a clearer picture of disease risk by asking other family members to come in for examination and genetic testing. Prior to the availability of the direct genetic test, clinics used a method called linkage testing. This older method requires a sample of DNA from a closely related affected relative, preferably a parent, for the purpose of identifying markers close to the HD gene. A version of the linkage method is sometimes still used for prenatal testing.
- Diagnostic imaging. In some cases, especially if a person’s family history and genetic testing are inconclusive, the physician may recommend brain imaging, such as computed tomography (CT) or, more likely, magnetic resonance imaging (MRI). As the disease progresses, these scans typically reveal shrinkage of the striatum and parts of the cortex, and enlargement of fluid-filled cavities within the brain called ventricles. These changes do not necessarily indicate HD, however, because they can occur in other disorders. Conversely, a person can have early symptoms of HD and still have normal findings on a structural CT or MRI scan.
What is predictive testing and how is it done?
A predictive or presymptomatic genetic test is an option for someone who has a family history of HD but shows no symptoms. Genetic testing makes it possible to predict with a higher degree of certainty whether or not the person will develop HD.
The decision to undergo presymptomatic testing is a highly personal and often difficult one to make. Common reasons that people choose to take the test include planning for marriage, children, education and career decisions, finances, stress, or simply to relieve uncertainty.
Centers across the U.S. offer genetic testing for HD, as well as pre- and post-test counseling. A list of such centers is available from the Huntington’s Disease Society of America at 1-800-345- HDSA (https://hdsa.org/). With the participation of families with HD, researchers and health professionals have developed guidelines for HD genetic testing. A team of specialists will help the at-risk person decide if testing is the right choice, and will carefully prepare the person for a negative, positive, or inconclusive test result. Whatever the results of genetic testing, the at-risk individual and family members can expect powerful and complex emotional responses. Because receiving test results may prove to be devastating, testing guidelines call for continued counseling even after the test is complete and the results are known.
In order to protect the interests of minors, including confidentiality, testing is not recommended for those under the age of 18 unless there is a compelling medical reason (for example, the child is exhibiting symptoms).
Prenatal testing is an option for people who have a family history of HD and are concerned about passing the disease to a child. Before requesting a prenatal test, and even before pregnancy, it is a good idea to seek advice from a genetic counselor. Prenatal testing can be done using either the direct method or the linkage method. As with adult testing, the direct method provides higher certainty. However, in addition to revealing the HD gene status of the fetus, the direct method also reveals the status of the at-risk parent.
Hopeful parents who do want to know their own HD gene status may opt for the linkage method, which is also known as prenatal exclusion testing. This test does not look for the HD gene itself but instead indicates whether or not the fetus has inherited a chromosome 4 mutation from the affected grandparent. If the mutation is present, the parents then learn that the fetus’s risk is the same as the at-risk parent (50 percent), but they learn nothing new about the parent’s risk. If the test shows that the fetus has inherited a chromosome 4 mutation from the unaffected grandparent, then the fetus has not inherited HD.
A person can have early signs of HD and still have normal findings on a CT or MRI scan.
Another option for parents is in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD). Briefly, a woman is given fertility drugs so that she produces many eggs at once, the eggs are fertilized by the man’s sperm in vitro (literally, “in glass”), and embryos are screened at a very early stage to determine if they carry the HD mutation. Embryos free of the mutation are then implanted in the woman’s uterus. Parents can choose not to know the exact results of genetic testing and thus are not forced to confront their own HD gene status. These procedures are available only at some specialized IVF clinics and require extensive counseling, preparation, and expense.
What treatments are available for HD?
A number of medications may be prescribed to help control emotional and movement problems associated with HD. It is important to remember however, that while medicines may help keep these clinical symptoms under control, there is no treatment to stop or reverse the course of the disease.
Most of the medications available for HD symptoms work by modulating neurotransmitters—the chemical messages that shuttle between neurons. For many of these drugs, their mechanisms of action against HD are not fully understood.
Tetrabenazine, which causes depletion of the neurotransmitter dopamine, is prescribed for treating Huntington’s-associated involuntary movements, as is deutetrabenazine.
Antipsychotic drugs, such as risperidone, olanzapine, or haloperidol, or other drugs such as clonazepam, may help to alleviate choreic movements and may also be used to help control hallucinations, delusions, and violent outbursts. Antipsychotic drugs, however, typically do not help with the muscle contractions associated with dystonia (involuntary muscle contractions that can cause slow, repetitive movement or abnormal postures), and may in fact worsen the condition, causing stiffness and rigidity.
For depression, physicians may prescribe citalopram, fluoxetine, sertraline, nortriptyline, or other compounds. Tranquilizers can help control anxiety and lithium may be prescribed to combat pathological excitement and severe mood swings.
Drugs used to treat the symptoms of HD may have side effects such as fatigue, sedation, decreased concentration, restlessness, or hyperexcitability, and should be only used when symptoms create problems for the individual. For those on medication, it may be difficult to tell if a particular symptom, such as apathy or memory loss, is a sign of the disease or a drug reaction.
What kind of care do individuals with HD need?
Cognitive problems are often the first changes that are noticed in HD. Evaluations conducted by clinical neuropsychologists, who specialize in cognitive assessment, can be helpful in clarifying an individual’s cognitive strengths and weaknesses, making safety recommendations and monitoring cognitive changes over time. Education about cognitive symptoms is also helpful for individuals and families. As the disease progresses, it is important to maintain regular daily routines for the person and to provide an environment with minimal distractions. Care should be taken not to isolate individuals who have become slow to engage in conversation or respond to questions. Speech therapy and other communication techniques may improve an individual’s ability to communicate and remain active in family and community life.
It is extremely important for a person with HD to maintain physical fitness as much as the course of the disease allows. Individuals who exercise and keep active tend to do better than those who do not. A daily regimen of exercise can help the person feel better physically and mentally. Although their coordination may be poor, individuals should continue walking, with assistance if necessary. Wearing special padding may also help reduce injuries in the event of a fall. Wearing sturdy shoes that fit well can help too, especially shoes without laces that can be slipped on or off easily.
Impaired coordination may make it difficult for people with HD to feed themselves and to swallow. As the disease progresses, people with HD may even choke. In helping individuals to eat, caregivers should allow plenty of time for meals. While some foods may require the addition of thickeners, other foods may need to be thinned. Some individuals may benefit from swallowing therapy, which is especially helpful if started before serious problems arise. Suction cups for plates, special tableware designed for people with disabilities, and plastic cups with tops can help prevent spilling. The individual’s physician can offer additional advice about diet and about how to handle swallowing difficulties or gastrointestinal problems that might arise, such as incontinence or constipation.
Proper nutrition is needed to ensure the individual with HD takes in enough calories to maintain body weight. Sometimes people with HD, who may burn as many as 5,000 calories a day through involuntary movements, require five meals a day to take in the necessary number of calories. Physicians may recommend vitamins or other nutritional supplements. When swallowing and nutritional problems become severe, some individuals and their families choose to use a feeding tube.
Individuals with HD are at special risk for dehydration and therefore require large quantities of fluids, especially during hot weather. Bendable straws can make drinking easier for the person. In some cases, water may have to be thickened with commercial additives to give it the consistency of syrup or honey.
What community resources are available?
Individuals and families affected by HD can take steps to ensure that they receive the best advice and care possible. Advocacy organizations including the Huntington’s Disease Society of America (HDSA) and the Hereditary Disease Foundation are excellent resources with information specific to HD. Some organizations support scientific workshops and research and provide information that enables families, health professionals and investigators to exchange information, learn of available services and benefits, and work toward common goals. HD support groups exist in many states across the country. State and local health service agencies can provide information on community resources and family support groups that may exist. Possible types of help include:
Legal and social aid. Since HD affects a person’s capacity to reason, make judgments, and handle responsibilities, individuals may need help with legal affairs. Wills and other important documents should be drawn up early to avoid legal problems when the person with HD may no longer be able to represent his or her own interests. Family members should also seek out assistance if they face discrimination regarding insurance, employment, or other matters.
Home care services. Caring for a person with HD at home can be exhausting, but part-time assistance with household chores or physical care of the individual can ease this burden. Domestic help, meal programs, transportation programs, nursing assistance, occupational therapy, or other home services may be available from federal, state, or local health service agencies.
Recreation and work centers. Many people with HD are eager and able to participate in activities outside the home. Therapeutic work and recreation centers give individuals an opportunity to pursue hobbies and interests and to meet new people. Participation in these programs, including occupational, music, and recreational therapy, can reduce the person’s dependence on family members and provides home caregivers with a temporary, much needed break.
Group housing. A few communities have group housing facilities that are supervised by a resident attendant and that provide meals, housekeeping services, social activities, and local transportation services for residents. These living arrangements are particularly suited to the needs of individuals who are alone and who, although still independent and capable, risk injury when they undertake routine chores like cooking and cleaning.
Institutional care. The individual’s physical and emotional demands on the family may eventually become overwhelming. While many families may prefer to keep relatives with HD at home whenever possible, a long-term care facility may prove to be best. To hospitalize or place a family member in a care facility is a difficult decision that may require professional counseling.
Finding the proper facility can itself prove difficult. Organizations such as the HDSA may have referrals to facilities that have had experience in the care of individuals with HD. Very few of these exist however, and even fewer have experience with individuals with juvenile or early-onset HD who require special care because of their age and symptoms.
Glossary of terms
- akinesia -decreased body movements.
- at risk -a description of a person whose mother or father has HD or has inherited the HD gene and who therefore has a 50]] -50 chance of inheriting the disorder.
- autosomal dominant disorder -a non sex linked disorder that can be inherited even if only one parent passes on the defective gene.
- basal ganglia -a region located at the base of the brain composed of four clusters of neurons, or nerve cells. This area is responsible for body movement and coordination. The neuron groups most prominently and consistently affected by HD—the pallidum and striatum are located here. See neuron, pallidum, striatum.
- caudate nuclei -part of the striatum in the basal ganglia. See basal ganglia, striatum.
- chorea -uncontrolled body movements. Chorea is derived from the Greek word for dance.
- chromosomes -the structures in cells that contain genes. They are composed of deoxyribonucleic acid (DNA) and proteins and, under a microscope, appear as rod -like structures. See deoxyribonucleic acid (DNA), gene.
- computed tomography (CT) - a technique used for diagnosing brain disorders. CT uses a computer to produce a high]] -quality image of brain structures. These images are called CT scans.
- cortex -part of the brain responsible for thought, perception, and memory. HD affects the basal ganglia and cortex. See basal ganglia.
- deoxyribonucleic acid (DNA) - the substance of heredity containing the genetic information necessary for cells to divide and produce proteins. DNA carries the code for every inherited characteristic of an organism. See gene.
- dominant -a trait that is apparent even when the gene for that disorder is inherited from only one parent. See autosomal dominant disorder, recessive, gene.
- gene -the basic unit of heredity, composed of a segment of DNA containing the code for a specific trait. See deoxyribonucleic acid (DNA).
- huntingtin -the protein encoded by the gene that carries the HD defect. The repeated CAG sequence in the gene causes an abnormal form of huntingtin to be formed. The function of the normal form of huntingtin is not yet known.
- kindred -a group of related persons, such as a family or clan.
- magnetic resonance imaging (MRI) -an imaging technique that uses radiowaves, magnetic fields, and computer analysis to create a picture of body tissues and structures.
- marker -a piece of DNA that lies on the chromosome so close to a gene that the two are inherited together. Like a signpost, markers are used during genetic testing and research to locate the nearby presence of a gene. See chromosome, deoxyribonucleic acid (DNA).
- mitochondria -microscopic, energy -producing bodies within cells that are the cells' "power plants."
- mutation -in genetics, any defect in a gene. See gene.
- myoclonus -a condition in which muscles or portions of muscles contract involuntarily in a jerky fashion.
- neuron -Greek word for a nerve cell, the basic impulse -conducting unit of the nervous system. Nerve cells communicate with other cells through an electrochemical process called neurotransmission.
- neurotransmitters -special chemicals that transmit nerve impulses from one cell to another.
- pallidum -part of the basal ganglia of the brain. The pallidum is composed of the globus pallidus and the ventral pallidum.See basal ganglia.
- positron emission tomography (PET) - a tool used to diagnose brain functions and disorders. PET produces three-dimensional, colored images of chemicals or substances functioning within the body. These images are called PET scans. PET shows brain function, in contrast to CT or MRI, which show brain structure.
- prevalence -the number of cases of a disease that are present in a particular population at a given time.
- putamen -an area of the brain that decreases in size as a result of the damage produced by HD.
- receptor -proteins that serve as recognition sites on cells and cause a response in the body when stimulated by chemicals called neurotransmitters. They act as on -and -off switches for the next nerve cell. See neuron, neurotransmitters.
- recessive -a trait that is apparent only when the gene or genes for it are inherited from both parents. See dominant, gene.
- senile chorea -a relatively mild and rare disorder found in elderly adults and characterized by choreic movements. It is believed by some scientists to be caused by a different gene mutation than that causing HD.
- striatum -part of the basal ganglia of the brain. The striatum is composed of the caudate nucleus, putamen, and ventral striatum. See basal ganglia, caudate nuclei.
- trait -any genetically determined characteristic. See dominant, gene, recessive.
- transgenic mice -mice that receive injections of foreign genes during the embryonic stage of development. Their cells then follow the "instructions" of the foreign genes, resulting in the development of a certain trait or characteristic. Transgenic mice can serve as an animal model of a certain disease, telling researchers how genes work in specific cells.
- ventricles -cavities within the brain that are filled with cerebrospinal fluid. In HD, tissue loss causes enlargement of the ventricles.
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